Porphobilinogen deaminase over-expression in hepatocytes, but not in erythrocytes, prevents accumulation of toxic porphyrin precursors in a mouse model of acute intermittent porphyria

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• 作者：Carmen Unzu ; Ana Sampedro ; Itsaso Mauleó ; n ; Lucí ; a Vanrell ; Juan Dubrot ; Rafael Enrí ; quez de Salamanca ; Gloria Gonzá ; lez-Aseguinolaza ; Ignacio Melero ; Jesú ; s Prieto ; Antonio Fontan
• 关键词：Acute intermittent porphyria ; Acute attack ; Porphyrin precursor excretion ; Motor coordination ; Bone marrow transplant ; Liver gene transfer
• 刊名：Journal of Hepatology
• 出版年：2010
• 出版时间：March 2010
• 年：2010
• 卷：52
• 期：3
• 页码：417-424
• 全文大小：733 K

文摘

Background & Aims

Acute intermittent porphyria (AIP) is characterized by hepatic porphobilinogen deaminase (PBGD) deficiency resulting in a marked overproduction of presumably toxic porphyrin precursors. Our study aimed to assess the protective effects of bone marrow transplantation or PBGD gene transfer into the liver against phenotypic manifestations of acute porphyria attack induced in an AIP murine model.

Methods

Lethally irradiated AIP mice were intravenously injected with 5 × 10⁶ nucleated bone marrow cells from wild type or AIP donor mice. To achieve liver gene transfer, AIP mice received via hydrodynamic injection plasmids expressing human PBGD or luciferase, driven by a liver-specific promoter.

Results

Erythrocyte PBGD activity increased 2.4-fold in AIP mice receiving bone marrow cells from normal animals. Nevertheless, phenobarbital administration in these mice reproduced key features of acute attacks, such as massively increased urinary porphyrin precursor excretion and decreased motor coordination. Hepatic PBGD activity increased 2.2-fold after hydrodynamic injection of therapeutic plasmid. Mice injected with the luciferase control plasmid showed a high excretion of porphyrin precursors after phenobarbital administration whereas just a small increase was observed in AIP mice injected with the PBGD plasmid. Furthermore, motor disturbance was almost completely abolished in AIP mice treated with the therapeutic plasmid.

Conclusions

PBGD deficiency in erythroid tissue is not associated with phenotypic manifestations of acute porphyria. In contrast, PBGD over-expression in hepatocytes, albeit in a low proportion, reduced precursor accumulation, which is the hallmark of acute porphyric attacks. Liver-directed gene therapy might offer an alternative to liver transplantation applicable in patients with severe and recurrent manifestations.